7
Strategies to Contain the Development and Consequences of Resistance

OVERVIEW

Managing the varied problems associated with antimicrobial resistance will require a coordinated response that includes participation by individuals, organizations, and governments at the local, state, national, and international levels. The focus of this session of the workshop was on examining current management efforts and highlighting additional steps needed to contain the development and consequences of resistance. In light of the increasing magnitude of the problem, participants universally agreed that implementing a comprehensive attack on antimicrobial resistance must proceed without further delay.

The primary blueprint for federal actions in the United States is the Public Health Action Plan to Combat Antimicrobial Resistance, issued in 2001 by a multiagency task force led by the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH). The plan has four focus areas: surveillance, prevention and control, research, and product development. Complete implementation of the plan will require adequate funding to support activities across a range of organizations.

Various public agencies and private organizations already are putting parts of the action plan into practice. The FDA is using its regulatory responsibility to ensure that drugs and other chemical agents used in both humans and animals do not pose unacceptable health risks, including risks that may arise as a result of antimicrobial resistance. In addition, the



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7 Strategies to Contain the Development and Consequences of Resistance OVERVIEW Managing the varied problems associated with antimicrobial resistance will require a coordinated response that includes participation by individuals, organizations, and governments at the local, state, national, and international levels. The focus of this session of the workshop was on examining current management efforts and highlighting additional steps needed to contain the development and consequences of resistance. In light of the increasing magnitude of the problem, participants universally agreed that implementing a comprehensive attack on antimicrobial resistance must proceed without further delay. The primary blueprint for federal actions in the United States is the Public Health Action Plan to Combat Antimicrobial Resistance, issued in 2001 by a multiagency task force led by the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH). The plan has four focus areas: surveillance, prevention and control, research, and product development. Complete implementation of the plan will require adequate funding to support activities across a range of organizations. Various public agencies and private organizations already are putting parts of the action plan into practice. The FDA is using its regulatory responsibility to ensure that drugs and other chemical agents used in both humans and animals do not pose unacceptable health risks, including risks that may arise as a result of antimicrobial resistance. In addition, the

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agency’s Center for Drug Evaluation and Research is exploring ways to enhance available approaches for the development of new antibiotics. Such activities include fostering early communication between the FDA and pharmaceutical companies, using the agency’s product labeling system to help educate physicians and other health care workers about antimicrobial resistance, and exploring methods for using data collected in clinical trials to make reliable inferences about a drug’s potential to trigger antimicrobial resistance. The CDC is implementing a variety of surveillance efforts and prevention and control activities, and is both undertaking and supporting applied research. In one effort, the agency has initiated the Campaign to Prevent Antimicrobial Resistance in Healthcare Settings, a nationwide program that targets clinicians, patient care partners, health care organizations, purchasers, and patients. The campaign centers around four basic strategies that front-line clinicians can use to prevent antimicrobial resistance. These strategies include preventing infections so as to directly reduce the need for antimicrobial exposure and the emergence and selection of resistant strains; diagnosing and treating infection properly, which will benefit patients and decrease the opportunity for development and selection of resistant microbes; using antimicrobials wisely, since optimal use will ensure proper patient care while avoiding overuse of broad-spectrum antimicrobials and unnecessary treatment; and preventing transmission of resistant organisms from one person to another. At the international level, the World Health Organization (WHO) in 2001 issued the WHO Global Strategy for Containment of Antimicrobial Resistance. The plan details a comprehensive framework of interventions designed to reduce the disease burden and the spread of infection, improve access to and improve use of appropriate antimicrobial agents, strengthen health systems and their surveillance capabilities, introduce and enforce regulations and legislation, and encourage the development of new drugs and vaccines. In implementing the plan, special priority will be given to educating the distributors, prescribers, and consumers of antimicrobial agents; to infection control measures aimed at preventing the dissemination of resistant strains; to quality assurance programs for antibiotics and other medicines; and to the establishment of functional and sustainable laboratories for antibiotic resistance surveillance. Much of the responsibility for implementing the WHO plan will fall on individual countries, and some of them—especially in the developing world—will need assistance. Toward this end, the Rational Pharmaceutical Management Plus Program, based at a nongovernmental organization, is helping to develop a systematic approach to designing national-level efforts to contain antimicrobial resistance. This approach will provide a framework by which various stakeholders, working with technical consultants

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when necessary, can assess policies, drug use, and levels of resistance in their countries, and then tailor a range of strategies for advocacy, policy development, and systems change. Although this approach is generic, its implementation likely will be country-specific and unfold in distinct ways, according to circumstances in each country. DEVELOPMENT OF THE PUBLIC HEALTH ACTION PLAN TO COMBAT ANTIMICROBIAL RESISTANCE AND CDC ACTIVITIES RELATED TO ITS IMPLEMENTATION David M. Bell, M.D. Office of the Director, National Center for Infectious Diseases Centers for Disease Control and Prevention, Atlanta, GA The Public Health Action Plan to Combat Antimicrobial Resistance To provide a blueprint for federal actions to address the emerging threat of antimicrobial resistance (AR), the Public Health Action Plan to Combat Antimicrobial Resistance (Part I Domestic Issues), was developed by a Federal Interagency Task Force on Antimicrobial Resistance and released in January 2001 (http://www.cdc.gov/drugresistance/actionplan/index.htm). The Task Force had been formed in 1999, after hearings held by Senators Frist and Kennedy, in recognition of the fact that addressing the multifaceted problem of antimicrobial resistance (AR) required action by multiple agencies and departments. Co-chaired by CDC, FDA, and NIH, the Task Force also includes the Agency for Healthcare Research and Quality, the Centers for Medicare and Medicaid Services, the Health Resources and Services Administration, the Department of Agriculture, the Department of Defense, the Department of Veterans Affairs, the Environmental Protection Agency, and, since 2001, the U.S. Agency for International Development. The plan was developed based on input from consultants from state and local health agencies, universities, professional societies, pharmaceutical companies, health care delivery organizations, agricultural producers, consumer groups, and other members of the public. It will be implemented incrementally, in collaboration with these and other partners, as resources become available. The plan has 4 focus areas: surveillance, prevention and control, research, and product development. Of 84 action items, 13 are designated top priority. Seven of the 13 are already underway, and 6 are planned to begin by 2003. Part I of the plan focuses on domestic issues; Part II, under development, will identify federal actions that more specifically address global AR issues in collaboration with the WHO and other part

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ners. The Task Force is continuing to meet to monitor implementation of the plan and will release annual progress reports and seek additional input at public meetings. CDC Activities CDC activities in 2001–2002 primarily implement action items in the surveillance and prevention and control (which includes prevention research) sections. Of CDC’s $25 million appropriation for AR in fiscal year 2001, about 75 percent was awarded extramurally, primarily to health departments and universities. This appropriation included approximately $12 million in new funds, of which $3.2 million was awarded through a new AR applied research grant program. CDC’s 2002 appropriation for AR, also $25 million, will primarily be used to continue ongoing activities summarized below. More information on these activities is available at www.cdc.gov/drugresistance. Surveillance In the United States, disease reporting is mandated by state laws, but most states do not require reporting of drug susceptibility information and the completeness of reporting varies. In collaboration with state health departments and other partners, CDC monitors resistance for several pathogens of public health importance and collects limited data on antimicrobial drug prescribing. For example, resistance in invasive S. pneumoniae infections is monitored on a population basis in 9 states or portions thereof through the Emerging Infections Programs, health care-acquired infections (e.g., S. aureus, enterococci, gram-negative bacteria) in approximately 300 hospitals, and foodborne pathogens such as Salmonella in 27 states in a joint project with the FDA and Department of Agriculture. In this project, resistance in foodborne pathogens and commensal organisms is also monitored in animals (and, beginning in 2001, in retail meat products). CDC-supported projects monitor drug resistance for several other pathogens or infections, for example, community-onset Staphylococcus aureus, tuberculosis, gonorrhea, influenza, Group B streptococci, Neisseria meningitidis, Helicobacter pylori, HIV, and malaria. These systems need enhancement using updated laboratory and informatics technologies, such as through the National Electronic Disease Surveillance System under development. The major problem, however, is that with the exception of tuberculosis, none provides even close to nationwide coverage. Most communities probably do not need sophisticated systems such as those that provide data to help develop and evaluate national prevention and control strategies. However, awareness of the extent to

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which resistance is present locally is helpful in guiding treatment decisions and in generating support for local public health interventions such as appropriate drug use and vaccine campaigns. To implement the action plan, CDC seeks to support coordinated national surveillance of drug resistance and use at two levels. One level would involve surveillance that could be done by most states, communities, and health care systems to meet local needs; the second level would consist of more specialized projects to address specific national needs in more detail and monitor emerging problems. Examples of new projects in 2001 include: Monitoring drug-resistant Staphylococcus aureus in the community in 5 states and a national population sample (the National Health and Nutrition Examination Survey). Increasing surveillance of enteric pathogens (through the National AR Monitoring System: Enteric Bacteria) from 17 to 25 states, characterizing and tracking resistance genes; monitoring drug-resistant bacteria in retail meat, and supporting new joint projects of state public health and veterinary laboratories. Monitoring resistance of influenza virus to newly licensed antiviral drugs. Beginning to develop a coordinated system to monitor antimicrobial drug use, through analyzing existing databases, identifying gaps, and exploring standardization of methods. Improving state, local, and health care system infrastructure to support development of local surveillance and enhance the capacity for electronic reporting. Reliable surveillance information—as well as patient care and safety— requires that front-line clinical laboratories detect emerging drug resistance accurately. Faced with evidence from surveys that this is frequently not the case (CDC, 2000), CDC is working with partners such as the Association of Public Health Laboratories and the American Society for Microbiology to develop training and proficiency testing programs. For example, in 2001, a new website “MASTER” was introduced that includes discussions of difficult cases in diagnostic microbiology, recommendations and references, and opportunities to question CDC microbiologists (www.phppo.cdc.gov/dls/master/default.asp). In its first year of operation, this site has received approximately 33,000 hits from 20 countries. The need for constant updating of clinical laboratory proficiency offers an opportunity for state public health laboratories to provide important leadership and strengthen their linkages with clinical laboratories. Through the National Laboratory Training Network and other programs, CDC’s goal is to work with partners to

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ensure training and proficiency in drug resistance testing and reporting for clinical laboratories in all states and territories. Prevention and Control Prevention and control of drug resistance primarily involve promoting appropriate use of antimicrobial drugs1 to extend their useful life and preventing infection transmission (e.g., through appropriate infection control and vaccine use). Prevention and control programs do not obviate the need for a constantly flowing “pipeline” of new drugs, as current drugs will inevitably become less effective with time due to resistance. CDC has been working with a variety of partners to promote appropriate antimicrobial use in the community (outpatient prescribing), in health care settings, and in agriculture (Bell, 2001). For acute infections in outpatients, a major objective is to reduce antimicrobial drug prescribing for illnesses for which these drugs offer no benefit (e.g., viral respiratory infections). In 1995, CDC launched a National Campaign for Appropriate Antibiotic Use that involves partnerships with state and local health departments, health care delivery organizations, health care purchasers and insurers, professional societies, consumer groups, and others. Often working through state-based coalitions, these partners implement coordinated educational and behavioral interventions directed to patients and clinicians, including public education programs, prescribing principles, clinical training materials, and aids (e.g., “viral prescription pads”) to help clinicians avoid prescribing an antibiotic when not indicated (see Figures 7-1 and 7-2). Data from controlled trials indicate that these interventions can be effective in reducing inappropriate antibiotic prescribing for respiratory infections in the United States, as has been reported in other countries—although resistance rates of respiratory pathogens, having reached a certain level, may not necessarily decline thereafter (Gonzales et al., 1999; Belongia et al., 2001; Finkelstein et al., 2001; Hennessy et al., 2002). Encouraging data from the National Ambulatory Medical Care Survey indicate that antibiotic prescribing rates for children seen in physician offices declined in the 1990s after having increased in the late 1980s (McCaig et al., 2002) (see Figure 7-3). Initially focused primarily on pediatrics, the 1   In the action plan, appropriate antimicrobial drug use is defined as use that maximizes therapeutic impact while minimizing toxicity and the development of resistance. In practice, this means prescribing antimicrobial therapy when and only when beneficial to a patient, targeting therapy to the desired pathogens, and using the appropriate drug, dose, and duration.

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FIGURE 7-1 Example of a poster, used in public education campaigns, promoting appropriate use of antimicrobial drugs, developed by CDC in partnership with the American Society for Microbiology. SOURCE: CDC, 2002.

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FIGURE 7-2 Example of a pamphlet, used in public education campaigns, promoting appropriate use of antimicrobial drugs, developed by CDC in partnership with the American Society for Microbiology. SOURCE: CDC, 2002.

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FIGURE 7-3 Trends in annual population-based rates of antimicrobial drug use at physician office visits for children under 15 years of age by selected infectious respiratory diseases and urinary tract infection: United States, 1989–2000. NOTE: Figures are based on 2-year averages. All trends shown are significant (p < 0.001), except sinusitis (p = 0.61) and UTI (p = 0.19). OM denotes otitis media. URI denotes upper respiratory infection. SOURCE: McCaig et al., 2002. campaign was expanded in 2001 to target prescribing for adults (Gonzales et al., 2001), to increase to 18 the number of state health departments funded to develop coalitions and to develop a national advertising campaign, a model medical curriculum, and HEDIS measures (benchmarks for health plans) for appropriate prescribing. Future goals include expanding the campaign to all states and major health plans and implementing the national advertising campaign. In health care settings, where infection with multi-drug-resistant organisms is a major patient safety issue, promoting appropriate antimicrobial drug prescribing is complicated by the higher stakes involved in treating sicker patients and the need to develop partnerships with a greater number of medical and surgical specialties involved in their care, as well as with other clinical staff and administrators. Prevent Antimicrobial Resistance, a campaign that emphasizes 12 evidence-based steps for diagnosis of infection, appropriate treatment, appropriate use of antibiotics, and preventing transmission, was launched by the CDC in March 2002, initially focusing on hospital care of adults. Future goals include implementing this campaign in other health care settings, for example, dialysis clinics and long-term care facilities, and for patients in all age groups, and evaluating and facilitating the appropriate use of new informatics technologies, for example, computerized decision support for online prescribing (Evans et al., 1998).

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Promoting appropriate antimicrobial drug use in agriculture and veterinary medicine has been complicated by longstanding disagreement between public health and agricultural communities regarding the benefits and risks of these uses, which may have economic implications for major industries. The American Veterinary Medical Association has developed principles for judicious therapeutic use of antimicrobials in veterinary medicine with input from CDC and FDA. CDC has also awarded cooperative agreements to four schools of veterinary medicine to assess the impact of antibiotic use in swine and dairy cattle, develop alternatives to the use of antimicrobials as growth promoters, and evaluate new practices to reduce resistant bacteria in food animals. Finally, CDC strongly supports the FDA’s proposals for a new framework to evaluate antimicrobial drugs used in food animal production and for withdrawal of approval for the use of fluoroquinolones in poultry as important steps toward protecting public health while ensuring the availability of antimicrobials needed for food-producing animals. Preventing transmission of infections (e.g., through appropriate use of vaccines, infection control in health care, food safety) reduces disease incidence and drug prescribing (Fridkin et al., 1999; Neuzil et al., 2000; Whitney et al., 2001). In 2001 CDC supported projects to evaluate the impact of pneumococcal conjugate vaccine in reducing infections with drug-resistant pneumococci, demonstration programs evaluating comprehensive approaches to infection control in health care settings in Chicago and Pittsburgh, and infection prevention and control research and evaluation programs at seven university-based Centers of Excellence in Healthcare Epidemiology. Regional approaches are important, as illustrated by the early recognition and successful control of the spread of vancomycin-resistant enterococci (VRE) in acute and long-term care facilities in the tri-state area surrounding Sioux City, Iowa. With leadership from the Sioux City health department and support from the Iowa, South Dakota, and Nebraska state health departments and CDC, health care institutions rigorously implemented surveillance and prevention and control guidelines and communi-cated freely. As a result, they were able to eliminate VRE from hospitals and drastically reduce VRE rates in long-term care facilities, an unprecedented success (Ostrowsky et al., 2001). Greater support for comprehensive regional programs such as this is a top priority of the action plan. Applied Research In 2001, CDC initiated a new AR applied research grant program. Based on external peer review, four grants totaling $3.2 million were awarded to universities for investigator-initiated research projects addressing: 1) prevention and control of AR in rural settings, and 2) resistance mechanisms and the role of drug use in promoting the spread of resistance

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in hospitals and from food animals to humans. Future goals of this research program include addressing additional Action Plan items through peer-reviewed, investigator-initiated proposals, for example, on diagnostic testing, infection control, drug and vaccine use, monitoring spread of resistance genes, impact of drug use in agriculture, clinical and economic outcomes of AR, and novel interventions. In summary, federal agencies now have a strategy and an action plan to address AR domestically—and a similar plan is being developed to address global resistance. Progress to date is encouraging, indicating that additional investments can be expected to pay dividends in converting AR from an urgent to a routine problem that does not compromise the availability of safe and effective therapy for patients today and in future generations. ANTIBIOTIC RESISTANCE: ENCOURAGING THE DEVELOPMENT OF NEW THERAPIES, PRESERVING THE USEFULNESS OF CURRENT THERAPIES Mark J. Goldberger, M.D., M.P.H. Center for Drug Evaluation and Research U.S. Food and Drug Administration, Rockville, MD Antibiotic resistance in a broad range of microrganisms has been steadily increasing. This has affected many of the therapies commonly used to treat infections caused by these organisms. This problem is not limited to bacterial infections but also includes fungi, parasites, and viruses. The focus of the following issues will be largely on antibacterial drugs; however, the approaches and issues would also be applicable to therapies for these other organisms. One obvious part of the solution to this problem is to develop new antimicrobials that are active against resistant organisms. There has already been progress in this area. Two new fluoroquinolone antibiotics, gatifloxacin (Bristol Myers Squibb, 1999) and moxifloxacin (Bayer, 1999), with increased activity against gram-positive bacteria have been recently approved. Members of three new classes of antimicrobials, the oxazolidinones (Pharmacia and Upjohn, 2000), streptogramins (Aventis, 1999), and ketolides (Ketek presented to advisory committee January 2003), have also either recently been approved or are far along in the drug development process. These are all examples of drugs that include some degree of activity against resistant organisms. Nonetheless, despite these advances serious concerns remain about our ability to successfully treat many infections due to either resistant gram-positive or gram-negative organisms. An ongoing focus in the coming months for staff in the Center for Drug Evaluation and

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technical aspects of a DTC, including selecting drugs for the formulary, managing drug expenditures, identifying drug use problems, and implementing interventions to improve drug use. An integral part of the DTC training is a field study where participants utilize skills learned in the course and apply them at local hospitals. The field study allows participants to see firsthand how a DTC would work in selecting drugs, identifying drug use problems, and implementing plans to improve drug use. An important part of the course focuses on developing DTC work plans. The course assists participants in developing comprehensive plans for starting or improving their local DTCs. These plans are monitored by RPM Plus staff members, who also provide technical assistance to help participants complete the plans over the ensuing months. DTC Website The DTC Website seeks to encourage former course participants to use what they have learned and to track their progress on work plans. RPM Plus staff monitor the site and provide technical assistance to individuals and teams as necessary. The Website provides course announcements, links to information sources, and access to work plans developed during the courses. The website also provides a discussion board that allows participants and facilitators to keep in contact. Achievements from DTC Courses RPM Plus has trained 117 participants from 35 countries in eight training courses since February 2001. DTC course participants have subsequently been active in improving drug management at the local and national level. DTCs have been implemented and are now more effective than previous drug management systems in selecting appropriate drugs for the formulary. Formularies have been evaluated and inappropriate drugs deleted, making procurement activities more efficient and less expensive. Reporting systems for adverse drug reactions (ADRs) have been upgraded and DTCs are reviewing spontaneous reports. Drug use studies and standard treatment guidelines are in use and are guiding strategies to improve drug use. RPM Plus will continue to hold DTC training courses while it monitors the work of past course participants. Promoting Infection Control Improvement Hospital-acquired infections are a major cause of preventable morbidity and mortality in developing countries worldwide, putting both patients

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and health care workers at risk. These infections also impose a high financial cost by increasing the length of hospitalization and requiring the use of additional, expensive laboratory tests and broad-spectrum antibiotics. They are often caused by AMR organisms that have developed due to poor infection-control and prevention practices and the overuse of antibiotics. There are many root causes of poor infection control and prevention in hospitals. There is a lack of both an infection-control infrastructure and training in basic infection control, and in many hospitals, basic hand hygiene and sanitation practices are substandard. The use of invasive devices and procedures, such as indwelling lines and catheters and implanted devices, can often be debilitating and even lethal when infection control practices are inadequate. In addition to the substantial impact on morbidity, mortality, and health care costs, there are other compelling reasons to focus on developing practical strategies for improving infection control and decreasing the emergence of AMR in hospitals: Hospitals are major incubators for resistant bacteria, because antimicrobial agents are commonly prescribed Hospitals can amplify resistance, because resistant bacteria spread quickly among vulnerable patients in facilities that are understaffed, over-crowded, or lack basic infection control practices Patients who acquire resistant infections in hospitals have the potential to disseminate these bacteria in their homes and communities RPM Plus is developing an infection-control quality improvement program (in collaboration with Harvard University) that will use local assessments, training, and intervention based on assessment results to improve infection control and decrease the rate of nosocomial infections at the hospital level. A distance-learning component will make it possible for many more institutions to take advantage of the program. The program’s objectives are to provide for: Development and use of assessment instruments to identify priority areas for site-specific interventions Training in continuous quality improvement techniques and methodologies Comprehensive training in infection control for teams and other clinical and administrative hospital personnel, available on a multimedia CD-ROM Development of a stand-alone infection control program, using CD-ROM, e-mail, and the Web, to establish or improve infection control

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systems by providing assessment instruments, training materials, coaching, and support to local team leaders. Joint Research Initiative to Improve Use of Medicines in Developing Countries RPM Plus is a partner with WHO, the Academy for Educational Development (AED), INRUD, and ARCH in the Joint Research Initiative to Improve Use of Medicines. The goal of the initiative is to build a body of evidence on effective drug use interventions in developing countries. Partners provide technical assistance to research groups in applying and testing interventions, as well as in pursuing publication of studies relevant to antimicrobial use. Current research activities are divided into three categories (see Table 7-1). Phase I studies are nearing completion, and Phase II studies are in the development and funding stage. Phase III studies will begin in late 2002. Other AMR Containment Support RPM Plus has developed a manual on hospital antimicrobial indicators, designed to help hospital staff evaluate and improve antimicrobial use in their institutions. The manual is useful in making comparisons of antimicrobial drug use in one hospital over time or between use in two or more hospitals. The RPM Plus portfolio also includes technical assistance activities for the Nepal national AMR program, which works to enhance AMR sentinel surveillance sites and improve drug management programs in the public and private sectors. Other AMR-related work includes support of INRUD activities including participation in Africa and Asia regional training courses on Promoting Rational Drug Use. RPM Plus interventions are designed to improve drug selection, appro TABLE 7-1 Joint Research Initiative to Improve Use of Medicine Phase I Phase II Phase III Research focused on improving the prescribing and dispensing behavior of health professionals Activities focused on improving the use of antimicrobials in communities and households Studies to evaluate the impact of specific national, district, and local policies that affect drug use, including strategies for scaling up

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priate use of drugs, and infection control practices at the local level, and to develop a process to implement these and other WHO global AMR containment strategies at the national level. With implementation of these key drug management programs, AMR containment strategies can be optimized. ANTIMICROBIAL RESISTANCE AND FUTURE DIRECTIONS Mary E. Torrence, D.V.M., Ph.D., D.A.C.V.P.M. USDA, Cooperative State Research Education and Extension Service, Washington, DC There are several common themes from the last two days. Emerging and re-emerging infectious diseases will continue to occur. These diseases will necessitate the use of current and new antimicrobials for treatment and are an important component of health care. The most important theme is that antimicrobial resistance exists, will continue to exist, and cannot be prevented or stopped. Our goal, therefore, must be to slow down its emergence and continue to develop new antibiotics that will take the place of those drugs that become useless because of resistance. No one would disagree that the public health action plan is a significant effort among various groups and represents a comprehensive strategy to address antimicrobial resistance (U.S. Government, 2001). However, one may wonder if this document will achieve the goals and action items outlined or whether the plan will remain just a comprehensive paper document. It is important that there is some measure of progress and a means of measuring the outcome or impact of the various actions and strategies. Continual feedback is needed so that revisions can be made and the plan remains responsive to the issues. In the spirit of the public health action plan, I will make my suggestions within each of the four categories: surveillance, research, prevention and control, and product development. Surveillance As we all know, there are multiple, existing surveillance efforts. Some are specifically targeted toward a particular disease or niche, for example, the hospital infectious control program, while others are more general in order to collect data that is representative. The starting question for the design of the best surveillance system has to be, “What is the question that we are trying to answer?” The answer drives the design of the system, the population sampled, and the collection of the data.

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The National Antimicrobial Resistance Monitoring System (NARMS) that began in 1996 provides a good framework for antimicrobial resistance surveillance (Tollefson et al., 1998). Would any of the other existing surveillance programs offer additional data? If so, how do we coordinate or integrate the programs or data? In the evaluation of NARMS, limitations must also be considered. Sampling differs from year to year. For example, isolates from healthy animals are taken from ongoing research projects and from the National Animal Health Monitoring System (NAHMS). The NAHMS studies vary each year as to geographic region represented, the animal species, and the number sampled. Samples taken from slaughter facilities also vary each year. For example, in 1999, campylobacter samples were only taken for 3 months; in 2000, samples were taken the entire year; and for 2001, samples were taken for 10 months (Torrence, 2001). These sampling differences make it difficult to make generalizations about the data and possible trends. There are currently two laboratories doing testing. Evaluations have been done so that the methods are standardized, and there is validity. If this system expands, standardization of methods is important. Expansion of laboratories may be necessary if this system is to provide quicker feedback of data. Currently results can lag more than a year behind. Another question is whether there is a role for animal diagnostic laboratories and clinical samples in the surveillance of antimicrobial resistance. Some of the funding available for capacity building for epidemiology and laboratories in public health could be used for animal diagnostic laboratories and epidemiological expertise. This enhancement would be useful for both antimicrobial resistance and for bioterrorism. Funding and human resources are needed for antimicrobial resistance surveillance. Research A common response for future directions is the request for more infrastructure, in terms of both expertise and funding. The U.S. Department of Agriculture (USDA) in relation to the CDC and the National Institutes of Health is largely underfunded even though USDA provides the majority of funding for antimicrobial resistance research in agriculture. For example, USDA’s Cooperative State Research Education and Extension Service funded $4 million in 1999 and $4.5 million in 2000. This funding came from food safety programs. The USDA’s Agricultural Research Service continues to budget for research to develop alternatives to antimicrobials, such as competitive exclusion products. The aim of competitive exclusion is to take advantage of the protective effect of normal healthy flora. Competitive exclusion products contain normal healthy microorganisms that compete with and replace pathogenic microorganisms, consequently, lowering the

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pathogenic burden. Significant issues of confidentiality of the data and the coordination of research have not been addressed. Specific Areas of Research There are basic research projects on the genetics of antimicrobial resistance and whether it occurs through gene transfer (e.g., integrons, plasmids) or through chromosomal mutation. However, it is also important to focus on applied research in an attempt to understand what is occurring in the populations. It is essential for intervention and mitigation strategies to identify critical control points along the continuum of food production. For example, management changes at the farm level will not prevent the transfer of pathogenic organisms if there is significant contamination at the processing or post-harvest level. Deboning and hide removal are two production steps that have potential for significant bacterial contamination. The majority of research has been done on important foodborne organisms such as E. coli O157:H7, Salmonella, and Campylobacter. But research is needed to evaluate the role of commensals in the development, persistence, and transference of antimicrobial resistance. Other bacteria that are more difficult to culture, such as anaerobes, must also be studied. Two primary questions in the study of antimicrobial resistance seem to be two of the simplest; yet, there seems to be no agreement on the answers. First, what is the unit of analysis? Is it the gene, bacterium, host, or population? Second, how do we measure antimicrobial resistance? Is it morbidity, the existence of a gene, or treatment failure? Determining the unit of analysis is also an issue if trying to evaluate drug usage in agriculture. Research is needed to determine which dosage, treatment regimen, or drug might be the most important in the development of resistance. Two recent drug use surveys reported different results because of disagreements in the measurement of drug use (Animal Health Institute, 2000; Lipsitch et al., 2002). Although economic research has been mentioned, much more needs to be done both in the human and agricultural sectors. For example, what are the costs and the benefits for certain management strategies on the farm? There has been an increased priority for doing risk assessments in food safety-related areas and in antimicrobial resistance but the methodologies are still primitive. This is particularly true in risk assessments of antimicrobial resistance because data are less available and the unit of measurement not determined. Finally, as more intervention and mitigation strategies emerge, there needs to be measurement of the outcome or impact of these strategies. This information will help in decision-making about production practices. It is

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time to move beyond simple prevalence studies to more applied practical studies. Prevention and Control There is still a great need for more rapid diagnostic tests and more rapid, sensitive detection methods. These methods could be used in finished food products and even in fruits and vegetables. Prudent use needs to be expanded to additional management strategies. There has been a large effort in the development of judicious use guidelines. But evidence of their dissemination and impact is lacking. If professionals have no interest or do not use them, then the existence of guidelines has no impact on antimicrobial resistance. Within the agricultural and veterinary medical community, the educational efforts need to be more aggressive and creative. For example, there could be information disseminated to pet owners to educate them that viral diseases, such as kennel cough, do not require the use of antibiotics and that less use of antibiotics is better for their pets and themselves. Educational research methodologies will help with the evaluation of the effect of current and future educational strategies as well as possible management and intervention approaches. There needs to be communication and feedback between education and research so there is continual improvement in both sectors. Product Development There are not the same financial incentives for veterinary drugs as human drugs so it is even less likely that new veterinary drugs will be developed or approved. Yet, new drug development for animal drugs may prove useful for human medicine in the common goal of finding new effective drugs. How can incentives be created? Currently most of the thinking is toward alternatives, alternative products and alternative management strategies. A significant effort in agriculture is toward alternative products such as competitive exclusion products, immune modulators, and vaccines. However, it is also important to concentrate on possible alternative management approaches. A more vigorous vaccination program or production design may decrease the amount of bacterial disease and the need for antimicrobials. Conclusions Antimicrobial resistance is not easily definable, which makes it more difficult to measure. A unit of analysis is needed. Antimicrobial resistance is

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not a product of one source and cannot be isolated in one niche of the world or the environment. It is the result of a confluence of humans, environment, microbes, and animals that are continually interacting with each other. These interactions fluctuate. Therefore, it is more important for researchers, professionals, and policy makers to work together to solve this problem rather than assign blame. Solutions in this area of resistance may come from previous experiences such as insecticide resistance. There needs to be coordination of the state, local, and federal governments as well as other groups such as industry and professional organizations. How do we better coordinate government, industry, and academia? How do we build trust so we can collaborate? There are many studies in academia that would provide important data and even samples for government initiatives. In conclusion, I think there are two final questions, “What is our ultimate goal regarding antimicrobial resistance?” Most importantly, “What are we willing to settle for?” I do not think we have answered these questions. REFERENCES Animal Health Institute. 2000. Survey indicates most antibiotics used in animals are used for treating and preventing disease. Press Release, February 14, 2000. [Online]. Available: http://www.ahi.org/news%20room/press%20release/2000/feb/antibiotic%20usage%20data.htm. Aventis. September 21, 1999. Dalfopristin; quinupristin injectable (Synercid). U.S. Patents: no unexpired patents. Bayer. December 10, 1999. Moxifloxacin tablet (Avelox). U.S. Patents 4,990,517, 5,607,942, 5,849,752. Bell DM. 2001. Promoting appropriate antimicrobial drug use: perspective from the Centers for Disease Control and Prevention. Clinical Infectious Diseases33 (Suppl 3):S245– S250. Belongia EA, Sullivan BJ, Chyou PH, Madagame E, Reed KD, Schwartz B. 2001. A community intervention trial to promote judicious antibiotic use and reduce penicillin-resistant Streptococcus pneumoniae carriage in children. Pediatrics108:575–583. Bristol Myers Squibb. December 17, 1999. Gatifloxacin injectable (Tequin). U.S. Patents 4,980,470, 5,880,283. CDC (Centers for Disease Control and Prevention). 1992. Public health focus: surveillance, prevention and control of nosocomial infections. Morbidity and Mortality Weekly Re port41:783–787. CDC. 1995. Recommendations for preventing the spread of vancomycin resistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Recommendations and Reports44(RR-12):1–13. CDC. 1999. Antimicrobial resistance: a growing threat to public health. [Online]. Available: http://www.cdc.gov/ncidod/hip/Aresist/am_res.htm. CDC. 2000. Laboratory capacity to detect antimicrobial resistance, 1998. Morbidity and Mortality Weekly Report48:1167–1171.

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